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Co-amoxiclav 500mg /125 mg film-coated Tablets


Each 500mg/125mg film-coated tablet contains 578.03 mg amoxicillin
trihydrate equivalent to 500 mg amoxicillin and 307.96 mg potassium
clavulanate equivalent to 125 mg clavulanic acid.
For full list of excipients see section 6.1.


Film coated tablet.
White to off-white film-coated oval shaped tablets debossed with RX713 on
one side and plain on the other side.




Therapeutic indications

Co-amoxiclav is indicated for the treatment of the following infections in adults and
children (see sections 4.2, 4.4 and 5.1):

Acute bacterial sinusitis (adequately diagnosed)
Acute otitis media
Acute exacerbations of chronic bronchitis (adequately diagnosed)
Community acquired pneumonia
Skin and soft tissue infections in particular cellulitis, animal bites,
severe dental abscess with spreading cellulitis.
Bone and joint infections, in particular osteomyelitis.

Consideration should be given to official guidance on the appropriate use of
antibacterial agents.


Posology and method of administration

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except
when doses are stated in terms of an individual component.
The dose of Co-amoxiclav that is selected to treat an individual infection should take
into account:
• The expected pathogens and their likely susceptibility to antibacterial
agents (see section 4.4)
• The severity and the site of the infection
• The age, weight and renal function of the patient as shown below.
The use of alternative presentations of Co-amoxiclav (e.g. those that provide higher
doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should
be considered as necessary (see sections 4.4 and 5.1).
For adults and children ≥ 40 kg, this formulation of Co-amoxiclav provides a total
daily dose of 1500 mg amoxicillin/375 mg clavulanic acid, when administered as
recommended below. For children < 40 kg, this formulation of Co-amoxiclav
provides a maximum daily dose of 2400 mg amoxicillin/600 mg clavulanic acid,
when administered as recommended below. If it is considered that a higher daily dose
of amoxicillin is required, it is recommended that another preparation of Coamoxiclav is selected in order to avoid administration of unnecessarily high daily
doses of clavulanic acid (see sections 4.4 and 5.1).
The duration of therapy should be determined by the response of the patient. Some
infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should
not be extended beyond 14 days without review (see section 4.4 regarding prolonged
Adults and children ≥40 kg
One 500 mg/125 mg dose taken three times a day.
Children < 40 kg
20 mg/5 mg/kg/day to 60 mg/15 mg/kg/day given in three divided doses.
Children may be treated with Co-amoxiclav film-coated tablets, suspensions or
paediatric sachets. Children aged 6 years and below should preferably be treated with
suspension or paediatric sachets.
No clinical data are available on doses of Co-amoxiclav 4:1 formulations higher than
40 mg/10 mg/kg per day in children under 2 years.
No dose adjustment is considered necessary.
Renal impairment

Dose adjustments are based on the maximum recommended level of amoxicillin.
No adjustment in dose is required in patients with creatinine clearance (CrCl) greater
than 30 ml/min.

Adults and children ≥ 40 kg
CrCl: 10-30
CrCl < 10 ml

500 mg/125 mg twice daily
500 mg/125 mg once daily
500 mg/125 mg every 24 hours, plus 500 mg/125 mg
during dialysis, to be repeated at the end of dialysis (as
serum concentrations of both amoxicillinand clavulanic
acid are decreased)

Children < 40 kg
CrCl: 10-30
CrCl < 10 ml

15 mg/3.75 mg/kg twice daily (maximum 500 mg/125
mg twice daily).
15 mg/3.75 mg/kg as a single daily dose (maximum 500
mg/125 mg).
15 mg/3.75 mg/kg per day once daily.
Prior to haemodialysis 15 mg/3.75 mg/kg. In order to
restore circulating druglevels, 15 mg/3.75 mg per kg
should be administered after haemodialysis.

Hepatic impairment
Dose with caution and monitor hepatic function at regular intervals (see sections 4.3
and 4.4).
Method of administration
Co-amoxiclav is for oral use.
Administer at the start of a meal to minimise potential gastrointestinal intolerance and
optimise absorption of amoxicillin/clavulanic acid.
Therapy can be started parenterally according the SPC of the IV-formulation and
continued with an oral preparation.



Hypersensitivity to the active substances, to any of the penicillins or to any of the

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another
beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).
History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid (see section


Special warnings and precautions for use

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be
made concerning previous hypersensitivity reactions to penicillins, cephalosporins or
other beta-lactam agents (see sections 4.3 and 4.8).
Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been
reported in patients on penicillin therapy. These reactions are more likely to occur in
individuals with a history of penicillin hypersensitivity and in atopic individuals. If an
allergic reaction occurs, amoxicillin/clavulanic acid therapy must be discontinued and
appropriate alternative therapy instituted.
In the case that an infection is proven to be due to an amoxicillin-susceptible
organisms(s) then consideration should be given to switching from
amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.
This presentation of Co-amoxiclav is not suitable for use when there is a high risk that
the presumptive pathogens have reduced susceptibility or resistance to beta-lactam
agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic
acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae.
Convulsions may occur in patients with impaired renal function or in those receiving
high doses (see section 4.8).
Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is
suspected since the occurrence of a morbilliform rash has been associated with this
condition following the use of amoxicillin.
Concomitant use of allopurinol during treatment with amoxicillin can increase the
likelihood of allergic skin reactions.
Prolonged use may occasionally result in overgrowth of non-susceptible organisms.
The occurrence at the treatment initiation of a feverish generalised erythema
associated with pustula may be a symptom of acute generalised exanthemous
pustulosis (AGEP) (see Section 4.8). This reaction requires Co-amoxiclav
discontinuation and contra-indicates any subsequent administration of amoxicillin.
Amoxicillin/clavulanic acid should be used with caution in patients with evidence of
hepatic impairment (see section 4.2). Hepatic events have been reported
predominantly in males and elderly patients and may be associated with prolonged

treatment. These events have been very rarely reported in children. In all populations,
signs and symptoms usually occur during or shortly after treatment but in some cases
may not become apparent until several weeks after treatment has ceased. These are
usually reversible. Hepatic events may be severe and, in extremely rare
circumstances, deaths have been reported. These have almost always occurred in
patients with serious underlying disease or taking concomitant medications known to
have the potential for hepatic effects (see section 4.8).
Antibiotic-associated colitis has been reported with nearly all antibacterial agents and
may range in severity from mild to life threatening (see section 4.8). Therefore, it is
important to consider this diagnosis in patients who present with diarrhoea during or
subsequent to the administration of any antibiotics. Should antibiotic-associated
colitis occur, amoxicillin/clavulanic acid should immediately be discontinued, a
physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal
products are contra-indicated in this situation.
Periodic assessment of organ system functions, including renal, hepatic and
haematopoietic function is advisable during prolonged therapy.
Prolongation of prothrombin time has been reported rarely in patients receiving
amoxicillin/clavulanic acid. Appropriate monitoring should be undertaken when
anticoagulants are prescribed concomitantly. Adjustments in the dose of oral
anticoagulants may be necessary to maintain the desired level of anticoagulation (see
section 4.5 and 4.8).
In patients with renal impairment, the dose should be adjusted according to the degree
of impairment (see section 4.2).
In patients with reduced urine output, crystalluria has been observed very rarely,
predominantly with parenteral therapy. During the administration of high doses of
amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in
order to reduce the possibility of amoxicillin crystalluria. In patients with bladder
catheters, a regular check of patency should be maintained (see section 4.9).
During treatment with amoxicillin, enzymatic glucose oxidase methods should be
used whenever testing for the presence of glucose in urine because false positive
results may occur with non-enzymatic methods.
The presence of Clavulanic acid in Co-amoxiclav may cause a non-specific binding of
IgG and albumin by red cell membranes leading to a false positive Coombs test.
There have been reports of positive test results using the Bio-Rad Laboratories
Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who
were subsequently found to be free of Aspergillus infection. Cross-reactions with nonAspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia
Aspergillus EIA test have been reported. Therefore, positive test results in patients
receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed
by other diagnostic methods.


Interaction with other medicinal products and other forms of interaction

Oral anticoagulants
Oral anticoagulants and penicillin antibiotics have been widely used in practice
without reports of interaction. However, in the literature there are cases of increased
international normalised ratio in patients maintained on acenocoumarol or warfarin
and prescribed a course of amoxicillin. If co-administration is necessary, the
prothrombin time or international normalised ratio should be carefully monitored with
the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral
anticoagulants may be necessary (see sections 4.4 and 4.8).
Penicillins may reduce the excretion of methotrexate causing a potential increase in
Concomitant use of probenecid is not recommended. Probenecid decreases the renal
tubular secretion of amoxicillin. Concomitant use of probenecid may result in
increased and prolonged blood levels of amoxicillin but not of clavulanic acid.


Pregnancy and lactation

Animal studies do not indicate direct or indirect harmful effects with respect to
pregnancy, embryonal/foetal development, parturition or postnatal development (see
section 5.3). Limited data on the use of amoxicillin/clavulanic acid during pregnancy
in humans do not indicate an increased risk of congenital malformations. In a single
study in women with preterm, premature rupture of the foetal membrane it was
reported that prophylactic treatment with amoxicillin/clavulanic acid may be
associated with an increased risk of necrotising enterocolitis in neonates. Use should
be avoided during pregnancy, unless considered essential by the physician.
Both substances are excreted into breast milk (nothing is known of the effects of
clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus
infection of the mucous membranes are possible in the breast-fed infant, so that
breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only
be used during breast-feeding after benefit/risk assessment by the physician in charge.


Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been
performed. However, undesirable effects may occur (e.g. allergic reactions, dizziness,
convulsions), which may influence the ability to drive and use machines (see section


Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea
and vomiting.
The ADRs derived from clinical studies and post-marketing surveillance with Coamoxiclav, sorted by MedDRA System Organ Class are listed below.
The following terminologies have been used in order to classify the occurrence of
undesirable effects.
Very common (≥1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1,000 to <1/100)
Rare (>1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)

Infections and infestations
Mucocutaneous candidosis
Overgrowth of non-susceptible organisms
Blood and lymphatic system disorders
Reversible leucopenia (including neutropenia)
Reversible agranulocytosis
Haemolytic anaemia
Prolongation of bleeding time and
prothrombin time1

Not known
Not known
Not known
Not known

Immune system disorders10
Angioneurotic oedema
Serum sickness-like syndrome
Hypersensitivity vasculitis

Not known
Not known
Not known
Not known

Nervous system disorders


Reversible hyperactivity
Gastrointestinal disorders
500 mg/125 mg film-coated tablets
Antibiotic-associated colitis4
Black hairy tongue
Hepatobiliary disorders
Rises in AST and/or ALT5
Cholestatic jaundice6
Skin and subcutaneous tissue disorders7
Skin rash
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Bullous exfoliative-dermatitis
Acute generalised exanthemous pustulosis (AGEP)9

Not known
Not known

Very common
Not known
Not known
Not known
Not known

Not known
Not known
Not known
Not known

Renal and urinary disorders
Interstitial nephritis
Not known
Not known
See section 4.4
See section 4.4
Nausea is more often associated with higher oral doses. If gastrointestinal
reactions are evident, they may be reduced by taking Co-amoxiclav at the
start of a meal.
Including pseudomembranous colitis and haemorrhagic colitis (see section
A moderate rise in AST and/or ALT has been noted in patients treated with
beta-lactam class antibiotics, but the significance of these findings is
These events have been noted with other penicillins and cephalosporins (see
section 4.4).
If any hypersensitivity dermatitis reaction occurs, treatment should be
discontinued (see section 4.4).
See section 4.9
See section 4.4
See sections 4.3 and 4.4



Symptoms and signs of overdose
Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may
be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been
observed (see section 4.4).
Convulsions may occur in patients with impaired renal function or in those receiving
high doses.
Amoxicillin has been reported to precipitate in bladder catheters, predominantly after
intravenous administration of large doses. A regular check of patency should be
maintained (see section 4.4).
Treatment of intoxication
Gastrointestinal symptoms may be treated symptomatically, with attention to the
water/electrolyte balance.
Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.




Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase
inhibitors; ATC code: J01CR02.
Mode of action
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or
more enzymes (often referred to as penicillin-binding proteins, PBPs) in the
biosynthetic pathway of bacterial peptidoglycan, which is an integral structural
component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to
weakening of the cell wall, which is usually followed by cell lysis and death.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant
bacteria and therefore the spectrum of activity of amoxicillin alone does not include
organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some
beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic
acid alone does not exert a clinically useful antibacterial effect.
PK/PD relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be
the major determinant of efficacy for amoxicillin.

Mechanisms of resistance
The two main mechanisms of resistance to amoxicillin/clavulanic acid are:
• Inactivation by those bacterial beta-lactamases that are not themselves
inhibited by clavulanic acid, including class B, C and D.
• Alteration of PBPs, which reduce the affinity of the antibacterial agent
for the target.
Impermeability of bacteria or efflux pump mechanisms may cause or contribute to
bacterial resistance, particularly in Gram-negative bacteria.
MIC breakpoints for amoxicillin/clavulanic acid are those of the European Committee
on Antimicrobial Susceptibility Testing (EUCAST)


Susceptibility Breakpoints (µg/ml)
Susceptible Intermediate Resistant

Haemophilus influenzae1
Moraxella catarrhalis1
Staphylococcus aureus 2
Coagulase-negative staphylococci 2

≤ 0.25


> 0.25

Streptococcus A, B, C, G5
Streptococcus pneumoniae3
Gram-negative Anaerobes1
Gram-positive Anaerobes1
Non-species related breakpoints1

≤ 0.25
≤ 0.5


> 0.25


The reported values are for Amoxicillin concentrations. For susceptibility
testing purposes, theconcentration of Clavulanic acid is fixed at 2 mg/l.
The reported values are Oxacillin concentrations.
Breakpoint values in the table are based on Ampicillin breakpoints.
The resistant breakpoint of R>8 mg/l ensures that all isolates with resistance
mechanisms are reported resistant.
Breakpoint values in the table are based on Benzylpenicillin breakpoints.
The prevalence of resistance may vary geographically and with time for selected
species, and local information on resistance is desirable, particularly when treating
severe infections. As necessary, expert advice should be sought when the local
prevalence of resistance is such that the utility of the agent in at least some types of
infections is questionable.

Commonly susceptible species

Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Gardnerella vaginalis
Staphylococcus aureus (methicillin-susceptible)£
Coagulase-negative staphylococci (methicillin-susceptible)
Streptococcus agalactiae
Streptococcus pneumoniae1
Streptococcus pyogenes and other beta-haemolytic streptococci
Streptococcus viridans group
Aerobic Gram-negative micro-organisms
Capnocytophaga spp.
Eikenella corrodens
Haemophilus influenzae2
Moraxella catarrhalis
Pasteurella multocida
Anaerobic micro-organisms
Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.
Species for which acquired resistance may be a problem
Aerobic Gram-positive micro-organisms
Enterococcus faecium $
Aerobic Gram-negative micro-organisms
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris
Inherently resistant organisms

Aerobic Gram-negative micro-organisms
Acinetobacter sp.
Citrobacter freundii
Enterobacter sp.
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas sp.
Serratia sp.
Stenotrophomonas maltophilia
Other micro-organisms
Chlamydophila pneumoniae
Chlamydophila psittaci
Coxiella burnetti
Mycoplasma pneumoniae
$ Natural intermediate susceptibility in the absence of acquired mechanism of
£All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic
Streptococcus pneumoniae that are resistant to penicillin should not be
treated with this
presentation of amoxicillin/clavulanic acid (see sections 4.2 and 4.4).
Strains with decreased susceptibility have been reported in some countries
in the EU with afrequency higher than 10%.


Pharmacokinetic properties

Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at
physiological pH. Both components are rapidly and well absorbed by the oral route of
administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at
the start of a meal. Following oral administration, amoxicillin and clavulanic acid are
approximately 70% bioavailable. The plasma profiles of both components are similar
and the time to peak plasma concentration (Tmax) in each case is approximately one
The pharmacokinetic results for a study, in which amoxicillin/clavulanic acid (500
mg/125 mg tablets three times daily) was administered in the fasting state to groups of
healthy volunteers are presented below.

Mean (± SD) pharmacokinetic parameters
Active substance(s)
Dose Cmax
Tmax *
(mg) (µg/ml) (h)

AUC (024h)

T 1/2

500 7.19
500/125 mg
± 2.26
Clavulanic acid
125 2.40
500 mg/125 mg
± 0.83
AMX – amoxicillin, CA – clavulanic acid
* Median (range)

1.5 (1.02.5)

± 8.87

± 0.20

1.5 (1.02.0)

15.72 ±

0.98 ±

Amoxicillin and clavulanic acid serum concentrations achieved with
amoxicillin/clavulanic acid are similar to those produced by the oral administration of
equivalent doses of amoxicillin or clavulanic acid alone.
About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is
bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for
amoxicillin and around 0.2 l/kg for clavulanic acid.
Following intravenous administration, both amoxicillin and clavulanic acid have been
found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and
peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the
cerebrospinal fluid.
From animal studies there is no evidence for significant tissue retention of drugderived material for either component. Amoxicillin, like most penicillins, can be
detected in breast milk. Trace quantities of clavulanic acid can also be detected in
breast milk (see section 4.6).
Both amoxicillin and clavulanic acid have been shown to cross the placental barrier
(see section 4.6).
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities
equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively
metabolized in man and eliminated in urine and faeces and as carbon dioxide in
expired air.
The major route of elimination for amoxicillin is via the kidney, whereas for
clavulanic acid it is by both renal and non-renal mechanisms.
Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one
hour and a mean total clearance of approximately 25 l/h in healthy subjects.
Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the
clavulanic acid are excreted unchanged in urine during the first 6 h after
administration of single Co-amoxiclav 250 mg/125 mg or 500 mg/125 mg tablets.
Various studies have found the urinary excretion to be 50-85% for amoxicillin and
between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic

acid, the largest amount of drug is excreted during the first 2 hours after
Concomitant use of probenecid delays amoxicillin excretion but does not delay renal
excretion of clavulanic acid (see section 4.5).
The elimination half-life of amoxicillin is similar for children aged around 3 months
to 2 years and older children and adults. For very young children (including preterm
newborns) in the first week of life the interval of administration should not exceed
twice daily administration due to immaturity of the renal pathway of elimination.
Because elderly patients are more likely to have decreased renal function, care should
be taken in dose selection, and it may be useful to monitor renal function.
Following oral administration of amoxicillin/clavulanic acid to healthy males and
female subjects, gender has no significant impact on the pharmacokinetics of either
amoxicillin or clavulanic acid.
Renal impairment
The total serum clearance of amoxicillin/clavulanic acid decreases proportionately
with decreasing renal function. The reduction in drug clearance is more pronounced
for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is
excreted via the renal route. Doses in renal impairment must therefore prevent undue
accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see
section 4.2).
Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function
monitored at regular intervals.

Preclinical safety data

Nonclinical data reveal no special hazard for humans based on studies of safety
pharmacology, genotoxicity and toxicity to reproduction.
Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid
demonstrate gastric irritancy and vomiting, and discoloured tongue.
Carcinogenicity studies have not been conducted with Co-amoxiclav or its




List of excipients
Tablet core
Cellulose microcrystalline
Sodium starch glycolate (Type A)
Silica colloidal anhydrous
Povidone (K 30)
Eudragit E100
Magnesium stearate
Tablet coating
Titanium dioxide (E171)
Macrogol 400



Not applicable

Shelf life

2 years
Tablets should be used within 5 days of opening of the pouch.

Special precautions for storage

Store in the original package in order to protect from light.
Do not store above 25°C.

Nature and contents of container

PVC/PVdC/Alu blister pack in pouch (Polyester film/Aluminium foil/Polyester
film/Polyethylene) with 1g sachet containing desiccant.
In packs of 10, 12, 14, 15, 16, 20, 21, 24, 30, 40 or 50 film-coated tablets.
Not all pack sizes may be marketed.

Special precautions for disposal

No special requirements.


Ranbaxy (UK) Limited
Building 4, Chiswick Park
566 Chiswick High Road
London, W4 5YE
United Kingdom



PL 14894/0017





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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.